ATRAID regulates the action of nitrogen-containing bisphosphonates on bone

Abstract

. CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/338350 doi: bioRxiv preprint first posted online Jun. 4, 2018; 3 Nitrogen-containing bisphosphonates (N-BPs) are the standard treatment for osteoporosis and several other bone diseases 11,12 . Certain N-BPs (pamidronate (Aredia®), zoledronate (Zometa®)) are also routinely prescribed to prevent skeletal complications in patients with multiple myeloma and with bone metastases from other malignancies, including breast and prostate cancer 13 . However, because N-BPs cause rare yet serious side-effects, such as atypical fractures and osteonecrosis of the jaw, many patients avoid taking them [5][6][7]11 , causing the number of prescriptions to plummet over 50% in the last decade 7,14 . Thus, there is a sizeable and growing need to better understand the genetic factors that might underlie the onand off-target clinical effects of the N-BPs.A goal of personalized medicine is to identify biomarkers that underlie drug responsiveness. In the case of the N-BPs, it can be said that there are limited personalization options owing to the limited number of genes implicated in the mechanism of action of N-BPs on bone. was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/338350 doi: bioRxiv preprint first posted online Jun. 4, 2018; 4 understanding of the molecular mechanisms by which N-BPs regulate the major bone cell types would be improved by further studies.To provide insight into the mechanism(s) of N-BPs action, we performed a genetic screen to identify human genes required for the anti-proliferative effects of N-BPs (Fig. 1a) Other genes identified in our alendronate haploid screen (SNTG1, PLCL1, and EPHB1) have been previously connected to N-BP action on bone cells and/or human bone diseases [28][29][30] . To systematically evaluate all "hits" we identified (i.e., the 185 genes with FDR p-value < 0.05, see Fig. 1b), we developed a computational approach utilizing a molecular biology-optimized version of PubMed (currently at ~27M records) to assess to what extent our haploid screen identified genes were cited as relevant to human studies that focus on bone (see "PubMed citation analysis" in the Methods section for details). We asked whether our alendronate haploid screen hits were mentioned in publications co-occurring with the term "bone" vs. other tissues along with identifiers of genome-wide screening, namely the strings, "GWAS" or "genome-wide" (Fig. 1c). Indeed, our alendronate screen hits were enriched in publications co-mentioning "bone" and genome-wide studies compared to control gene sets (Fig. 1d, Supplementary Table 1b). This . CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed...

Cell fitness is an omniphenotype

“…We recently published a proof-of-concept of this idea -which can be thought of as an expanded definition of synthetic interaction testing -with the osteoporosis drugs, nitrogen-containing bisphosphonates (N-BPs) (23,35,36). In this work, we identified a gene network, ATRAID-SLC37A3-FDPS, using cell-fitness-based, drug interaction screening with the N-BPs, and subsequently demonstrated this network controls N-BP responses in cells, in mice, and in humans (23,35,36). In this case, N-BPs and FDPS were the known, K, and ATRAID and SLC37A3 were the unknown, U, we discovered.…”

Epigenetic Regulators Involved in Osteoclast Differentiation

“…One of the most common types of drugs prescribed to patients with bone diseases are bisphosphonates, specifically nitrogen-containing bisphosphonates such as alendronate [ 85 ]. Nitrogen containing bisphosphonates inhibit prenylation of the GTP binding protein Ras [ 86 ].…”

“…Nitrogen containing bisphosphonates inhibit prenylation of the GTP binding protein Ras [ 86 ]. The molecular targets of bisphosphonates are enzymes of the mevalonate pathway or prenyl protein transferases such as farnesyl diphosphate synthase (FDPS), thereby affecting protein prenylation which ultimately leads to osteoclasts undergoing apoptosis [ 85 , 86 ]. The mevalonate pathway provides metabolites for post translational modifications which can result in changes in HDACs, microRNAs and DNA methyltransferases.…”

Sphingolipid Biosynthesis Inhibition As A Host Strategy Against Diverse Pathogens

“…While our initial validation of sertraline hits suggested that we could detect strong genetic interactions in genome-wide screens with CADs (Figure S1B), there are valid concerns about whether using micromolar (µM) doses in cancer cell lines with cell fitness as a readout can give insight into in vivo biology for drugs such as these CADs, which are not indicated for cancer. However, we have previous demonstrated the success of this approach with the bisphosphonates (1,2,27), which suggest that it might yield meaningful results for the CADs as well (14).…”

“…A comparison of the six CADs we screened vs. genome-scale screens (as opposed to targeted screens, e.g., involving the kinome) we and others performed with non-CADs shows the specificity of the CADs signature ( Figure 1C) (1)(2)(3)(4)(5). There were nineteen genes that scored on average an absolute value of at least 2.5 standard deviations away from the mean for the six CADs screens (hereafter referred to as pooled variance, PV) ( Figure 1C, Table S1).…”